tbuckley/cabot-search huggingface dataset:
Abstract 3252: Tumor treating fields suppression of ciliogenesis enhances temozolomide toxicity
Authors: Ping Shi, Jia Tian, Brittany Ulm, Julianne Mallinger, Habibeh Khoshbouei, Loic Deleyrolle, Matthew Sarkisian
Journal: Cancer Research (2022)

Abstract Tumor Treating Fields (TTFields) are low intensity, alternating intermediate frequency (200kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer cells over normal cells, or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation, and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low and high grade patient glioma cell lines that TTFields ablated cilia within 24 hours. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons and multiciliated ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Moreover, the inhibitory effects of TTFields and TMZ on tumor cell recurrence correlated with the relative timing of TMZ exposure to TTFields and ARL13B positive cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest TTFields efficacy may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment. Citation Format: Ping Shi, Jia Tian, Brittany Ulm, Julianne Mallinger, Habibeh Khoshbouei, Loic Deleyrolle, Matthew Sarkisian. Tumor treating fields suppression of ciliogenesis enhances temozolomide toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3252.
Abstract 4181: CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis
Authors: Naema Nayyar, Mohini Singh, Magali de Sauvage, Nazanin Ijad, Ashish Dahal, Jane Chuprin, Michael Brehm, Priscilla Brastianos
Journal: Cancer Research (2022)

Abstract While immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancers, few of the 30% of cancer patients who develop brain metastases benefit from immunotherapy. Inhibition of CDK4/6 pathway - altered in &amp;gt;50% of brain metastatic patients - can reportedly increase tumor inflammation and sensitize extracranial tumors to ICI. To determine whether intracranial tumors can be similarly sensitized, we studied efficacy of combination CDK4/6 inhibitor Abemaciclib and ICI in immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial murine tumors that are ICI-resistant. 8-week-old female C57BL/6 mice received subcutaneous injections of 2x105 YUMM1.7 or B16-F10 melanoma cells 3 days prior to intracranial injections of 1x104 YUMM1.7-FmC (firefly luciferase-tagged) cells or 5x103 B16-F10 cells respectively. 8-week-old female BALB/C mice similarly received 2x105 4T1 mammary carcinoma cells in mammary fat pad 3 days prior to intracranial injections with 2x104 4T1-FmC cells. Mice were randomized into 4 treatment groups (n=5-7/group): Abemaciclib monotherapy (administered daily), anti-PD-1 monotherapy (every 3 days), Abemaciclib and anti-PD-1 (combination therapy), and treatment with vehicle and isotype-matched antibody as control. In all 3 tumor models, extracranial tumor growth was significantly reduced compared to control mice following combination therapy (P&amp;lt;0.05 for all), while Abemaciclib monotherapy only reduced growth of subcutaneous YUMM1.7 tumors (P&amp;lt;0.05). Intracranial tumor growth, calculated using bioluminescence imaging early-in-treatment and post-treatment, was significantly reduced compared to control-treated tumors following combination therapy in both YUMM1.7-FmC and 4T1-FmC models (P&amp;lt;0.05 for both). In mice bearing B16-F10 tumors, where overall survival was used as an indirect measure of intracranial tumor growth, combination therapy improved survival (p&amp;lt;0.05) compared to both control and Abemaciclib monotherapy arms. These results indicate CDK4/6 inhibition with Abemaciclib can improve both extracranial and intracranial responses to ICI and sensitize brain metastases to immunotherapy. Our pre-clinical findings warrant further investigation to determine whether this combination approach can improve patient outcomes. Citation Format: Naema Nayyar, Mohini Singh, Magali de Sauvage, Nazanin Ijad, Ashish Dahal, Jane Chuprin, Michael Brehm, Priscilla Brastianos. CDK4/6 inhibition with Abemaciclib improves intracranial and extracranial response to checkpoint blockade in pre-clinical models of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4181.
Abstract 1421: Non-invasive early detection of pancreatic ductal adenocarcinoma using methylation signatures in circulating tumor DNA
Authors: Athurva J. Gore, Justin Dang, Alan Fung, Bin Xie, Rui Liu
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate primarily due to late onset of symptoms and rapid progression. Early symptoms, which include abdominal and back pain, diarrhea, weight loss, and jaundice are non-specific for PDAC and may be associated with other gastrointestinal diseases. PDAC lacks reliable and accurate tests for early detection. We aimed to discover biomarkers carrying a PDAC-specific DNA methylation signature in blood cell-free DNA, and to develop and validate a non-invasive test for PDAC detection. Methods: Reduced representative bisulfite sequencing (RRBS) was previously performed on tissue and plasma samples from PDAC patients and healthy individuals to identify PDAC-specific methylation markers. These markers were combined with previously reported cancer methylation markers for a second round of marker screening. The resulting markers were utilized to develop a targeted methylation sequencing assay for plasma DNA, designated as PDACatch. The PDACatch assay was validated on an independent sample set to demonstrate its efficacy for pancreatic cancer methylation signature detection. Results: The PDACatch assay was performed on 91 PDAC plasma and 84 healthy plasma samples obtained from commercial biobanks. In this independent verification sample set, the PandaX assay predicted PDAC from healthy with AUC of 0.91; accuracy remained high for classification of both stage I and early-stage (I/IIa) samples. Conclusion: The PDACatch assay, a ctDNA methylation based blood test, achieved a high accuracy for detecting PDAC at early stages, indicating its potential in screening effectiveness. Citation Format: Athurva J. Gore, Justin Dang, Alan Fung, Bin Xie, Rui Liu. Non-invasive early detection of pancreatic ductal adenocarcinoma using methylation signatures in circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1421.
Abstract 5368: Role of spatially distinct tumor fibroblast in erlotinib resistance
Authors: Gina Bouchard, Sylvia K. Plevritis
Journal: Cancer Research (2022)

Abstract Metabolic reprogramming toward the hexosamine biosynthesis pathway (HBP), an understudied glucose pathway leading to O-glycosylation, is associated with poor survival in the lung adenocarcinoma (LUAD). We found that this metabolic switch happens primarily in Cancer-Associated Fibroblasts (CAFs), an “activated” phenotype associated with bad outcomes in cancer. We show that spatially distinct CAFs harvested from the tumor edge (Tumor-Adjacent-Fibroblasts; TAFs) of LUAD specimens vs the tumor core (Tumor Core Fibroblasts; TCFs) successfully protect cancer cells from erlotinib treatment, as measured by proliferation (ki67), migration (podoplanin) and resistance (Multidrug Resistance 1; MDR1) markers. However, while TCFs increase O-GlcNAcylation in cancer cells, a type of dynamic O-glycosylation, TAFs decrease O-GlcNAcylation in a subpopulation of cells. Interestingly, this subpopulation of cancer cells shows an increase of partial EMT features, as well as proliferation. In addition, we find this population of cancer cells to overexpress the MDR1 transporter, known to actively export erlotinib outside the cell. These results were reproduced in a novel in vitro assembloid model using patient-derived organoids and primary fibroblast mixtures that allow us to characterize cancer and spatially distinct stromal cells in response to erlotinib treatment. Overall, our preliminary results show that TAFs from the invasive leading edge of lung tumors decrease O-GlcNAcylation in cancer cells, which promotes erlotinib resistance. In summary, O-GlcNAcylation represents a potential avenue to mitigate resistance induced by tumor-stroma crosstalk and improve cancer treatment. Citation Format: Gina Bouchard, Sylvia K. Plevritis. Role of spatially distinct tumor fibroblast in erlotinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5368.
Abstract 6039: Application of triple negative breast cancer patient-derived organoid and xenograft model for drug screening
Authors: Seungyeon Ryu, Hoe Suk Kim, Jung Eun KIM, So-Hyun Yoon, Sangeun Lee, Moonjou Baek, Han-Byoel Lee, Dong Woo Lee, Bosung Ku, Wonshik Han
Journal: Cancer Research (2022)

Abstract Background: Breast cancer Patient Derived Organoids (PDOs) and patient-derived xenografts (PDXs) which recapitulate the tumor heterogeneity and molecular signatures of original tumor tissue, are useful tools to enable greater precision of both approved and experimental medicines through personalized therapeutic approaches. We focus on use of ex vivo PDOs, PDX-derived organoids (PDXOs), and vivo PDXs models for drug testing and personalized therapy. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in breast cancer. Methods: Fresh surgical specimens of primary TNBC breast tumor (N=3) were used for PDOs. PDOs and PDX-derived organoids (PDXOs) were cultured in previously reported media compositions based on ECM hydrogel. PODs and PDXOs were subjected to drug screening for 22 anticancer drugs including chemoreagents and targeted drugs in the 3D HTS system. Drug sensitivity was tested in triplicate in different concentration ranges for 7 days. The IC50 for each drug was calculated by a sigmoidal dose-response curve, using the GraphPad Prism 9 program. For drug screening in PDXs models, PDOs were injected into the fourth mammary fat pads of NOD.Cg-Prkdcscid Il2rgtm1wjl/SzJ mice. WEE1 inhibitor (AZD1775) was administered by oral gavage (AZD1775, 30 mg/kg) for 3 weeks. Immunostaining of ER, PR, Her2, CK5 and Ki67 was performed in PODs, PODXs and PDX tumor tissues. Results: All PDOs, PDXs, and PDXOs were ER-, PR- and HER2- negative. PDOs and PDXOs (172T, 185T, 207T) showed differential response to 22 anticancer drugs. In PDOs and PDXOs models, 172T and 207T PDOs and PDXOs are highly sensitive to AZD1775, but 185T PDOs and PDXOs less sensitive or never respond to treatment with AZD1775 (10 µM). In PDX models, treatment with AZ1775 decreased tumor growth (P&amp;lt;0.0079) as well as distance metastasis in 207T-PDX mice, whereas in 172T- and 185T-PDX mice, the tumor growth and metastasis were not reduced compared with the vehicle group. Conclusion: Consequently, PDOs, PDXOs and PDXs recapitulated immunohistological signatures of original tumor tissues. The results of WEE1 inhibitor response between PDOs, PDXOs and PDXs were consistent. This study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified drugs. Citation Format: Seungyeon Ryu, Hoe Suk Kim, Jung Eun KIM, So-Hyun Yoon, Sangeun Lee, Moonjou Baek, Han-Byoel Lee, Dong Woo Lee, Bosung Ku, Wonshik Han. Application of triple negative breast cancer patient-derived organoid and xenograft model for drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6039.
Abstract 5777: Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients
Authors: Jingnan Shen, Xiaomo Li, Xianbiao Xie, Si Liu, Tonghui Ma
Journal: Cancer Research (2022)

Abstract Background: Sarcomas represent a rare and heterogeneous group of soft tissue and bone cancers, including more than 100 histological subtypes. Although genomic profiling has identified oncogenic fusion genes as the major molecular drivers of many sarcoma subtypes, direct targeting of these fusion genes is clinically challenging and novel treatment approaches are needed. Methods: To explore new therapeutic targets in sarcoma, we performed germline testing of 148-cancer predisposition genes (OncoPanscan࣪, Genetronhealth) on genomic DNA from a cohort of 822 unselected Chinese sarcoma patients. Results: The median age of this cohort was 45 (1-88) years, and 84% were soft tissue sarcoma (STS), 16% were osteosarcoma. 9.3% (n =82) of patients harbored at least one predicted pathogenic germline variant in 37 cancer disposition genes including APC, BRCA1, BRCA2, CDKN2A, CHEK2, DICER1, MSH6, PMS2, SBDS, SMARCA4, and TP53. Twenty-four (2.9%) patients had a variant that mapped to a known sarcoma-associated cancer predisposition syndrome gene (CHEK2, DICER1, NF1, RECQL4, SMARCA4, TP53, WRN). The most frequently mutated genes are involved in the DNA damage repair pathway, with a prevalence of 6.3% (n =52). Twelve patients carried pathogenic mutations in TP53, which was associated with cancer-predisposing Li-Fraumeni syndrome (LFS). Interestingly, we also observed 12 patients harboring the same SBDS c.258+2T&amp;gt;C variant. Biallelic SBDS mutations were linked to Shwachman-Diamond Syndrome (SDS) associated with leukemia predisposition. Additionally, four patients carried pathogenic mutations in SMARCA4 (n =2) and SMARCE1 (n =2), two genes encoding key components of the BAF chromatin-remodeling complex. Patients with pathogenic SMARCA4 germline variants could participate in clinical trials of EZH2 inhibitor tazemetostat. Four patients harbored pathogenic germline variants in core homologous recombination genes (BRCA1/2 and PALB2), which may be targeted with platinum-based chemotherapy or PARP inhibitor olaparib. Conclusions: In summary, our genomic profiling approach revealed novel predisposition variants associated with sarcoma, and some of them can serve as therapeutic targets for future clinical investigation. Our work provided proof of principle that sarcoma patients may benefit from genetic counseling and participate in genomically-matched clinical trials. Citation Format: Jingnan Shen, Xiaomo Li, Xianbiao Xie, Si Liu, Tonghui Ma. Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5777.
Abstract 1508: Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin
Authors: Jüri Reimand, Oliver Ocsenas
Journal: Cancer Research (2022)

Abstract Cancer genomes are shaped by mutational processes with complex spatial variation at multiple scales. However, the underlying mechanisms of this mutagenesis and its functional and genetic determinants remain poorly understood. Somatic regional mutagenesis is known to correlate with DNA replication timing and chromatin accessibility; however, these studies have used epigenetic information from common cell lines while the epigenomes of primary human cancers remain uncharacterized in this context. Here we model megabase-scale mutation frequencies of single nucleotide variants (SNVs) in thousands of whole cancer genomes using hundreds of genome-wide profiles of chromatin accessibility and replication timing spanning primary cancer samples, normal tissues, and cell lines. Using a machine learning framework, we show that CA profiles of primary cancers, rather than those of normal cells, predict regional mutagenesis and single base substitution (SBS) signatures in most cancer types. Thus the majority of passenger mutations follow the epigenetic landscapes of transformed cells of matching cancer sites and tissues. Mutational signatures associated with carcinogen exposure, as well as signatures of unknown origin, show the strongest associations with epigenomes while associations with endogenous signatures are weaker. In most cases, overall mutation burden and SBS signatures inversely correlate with chromatin accessibility, however certain signatures are instead enriched in chromatin-accessible elements. Lastly, the genomic regions with excess mutations unexplained by the epigenetic profiles in our models likely represent a combination of localized mutagenesis and positive selection of functional oncogenic mutations. Our computational models highlight an enrichment of known driver mutations, point out novel intergenic regions with putative non-coding drivers, and indicate an over-representation of developmental and lineage-specific genes in these frequently mutated genomic regions. These results characterize the complex interplay of mutational processes, genome function, and somatic evolution in cancer and its tissues of origin, and also outline strategies for distinguishing driver and passenger mutations. Citation Format: Jüri Reimand, Oliver Ocsenas. Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1508.
Abstract 5551: QLS31905, an anti-claudin 18.2/CD3 bispecific antibody for claudin 18.2-positive gastric cancer
Authors: Jiahua Jiang, Meimei Si, Xiao Luo, Yun Wu, Yongjun Li, Xiaodan Yan
Journal: Cancer Research (2022)

Abstract Claudin 18.2 is a quadruple transmembrane protein with a complex structure and highly specific expression in gastric and pancreatic cancers. It is suggested that claudin 18.2 is an ideal target for cancer therapy. Anti-claudin 18.2 antibody IMAB362 has achieved remarkable success in the latest clinical trials. Multiple anti-claudin 18.2 monoclonal antibodies and chimeric antigen receptor T-cell therapy targeting claudin 18.2 have also entered phase I clinical trials. CD3 is a receptor that is present on the surface of T cells and is involved in the antigen recognition by T cells as well as in signal transduction. Anti-claudin 18.2/CD3 bispecific antibody can recruit T cells to tumor sites, activating T cells to kill tumor cells with high claudin 18.2 expression to improve efficacy. Here, we describe a new T cell-redirecting antibody (QLS31905) that is bispecific for claudin 18.2 and CD3. QLS31905 showed a potent in vitro cytotoxic activity against claudin 18.2-positive engineered cell lines HEK293-hCLDN18.2 and NCI-N87 CLDN18.2 as well as superior in vivo efficacy in humanized NCI-N87 CLDN18.2 model. Furthermore, QLS31905 was safe and well tolerated in a 4-week repeated dose (up to 10 mg/kg) toxicity study in cynomolgus monkeys. In vitro cytokine release was lower in the QLS31905 group than that in the AMG 910 (another anti-claudin18.2/CD3 bispecific antibody) group. Overall, these data suggested that QLS31905 has similar efficacy to AMG 910 and is safer. QLS31905 may be an effective and clinically valuable treatment for patients with claudin 18.2-positive gastric cancer. Citation Format: Jiahua Jiang, Meimei Si, Xiao Luo, Yun Wu, Yongjun Li, Xiaodan Yan. QLS31905, an anti-claudin 18.2/CD3 bispecific antibody for claudin 18.2-positive gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5551.
Abstract 1936: MethylationToRegulation: A deep-learning approach to infer chromatin properties from DNA methylomes
Authors: Daniel K. Putnam, Brian J. Abraham, Xiang Chen
Journal: Cancer Research (2022)

Abstract Gene regulation is critical for cell identity, and its dysregulation is a defining characteristic of common diseases including cancers. Although promoter activity is a strong predictor of gene expression, activities at other regulatory elements, including enhancers and super-enhancers (SE), are major contributors to gene regulation. For example, distinct transcription factor-regulating SEs define neuroblastoma (NB) subtypes with distinct clinical outcomes. However, technical limitations largely prevent ChIP-seq based enhancer/SE activity profiling in primary patient samples. We previously developed MethylationToActivity (M2A) and demonstrated that high-order DNA methylation (DNAm) features are strong predictors of promoter activity measured by ChIP-seq. This tool is important because genomewide DNAm assays are widely used in clinic to classify tumors and stratify patients on clinical trials. However, it is limited by its reliance on known gene position annotations. Here we present MethylationToRegulation (M2R), a method that utilizes a convolutional neural network (CNN)-based deep learning framework to infer intergenic enhancer/SE activities from DNA methylomes. We obtained paired WGBS and H3K27ac ChIP-seq data for 16 pediatric NB samples profiled in the Pediatric Cancer Genome Project. M2R was trained on 6 samples and tested on the remaining 10 samples. It achieved an average relative prediction accuracy of 84% on test samples when compared to the H3K27ac ChIP-seq replicate consistency from the ENCODE project. We adapted the Rank Ordering of Super-Enhancers algorithm to interpret H3K27ac signals inferred from DNA methylomes to identify SEs. M2R faithfully captured subtype-defining SEs with high specificity, including those associated with master NB transcription factors. Our results demonstrate that M2R accurately quantifies enhancer/SE activities and infers critical epigenetic marks from DNA methylomes. Application of M2R will enable the profiling of epigenetic dysregulation in patient tumor samples, seeking to improve clinical outcomes. Citation Format: Daniel K. Putnam, Brian J. Abraham, Xiang Chen. MethylationToRegulation: A deep-learning approach to infer chromatin properties from DNA methylomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1936.
Тези науково-практичної конференції зміжнародною участю «X наукова сесія Інституту гастроентерології НАМН України. Новітні технології в теоретичній таклінічній гастроентерології» (16–17 червня 2022 р., м. Дніпро, Україна)
Authors: No Authors
Journal: GASTROENTEROLOGY (2022)

No abstract